FIELD OF THE INVENTION
The present invention relates to an improved process for preparing compressed methylcellulose containing tablets which meet USP disintegration standards.
BACKGROUND OF THE INVENTION
The history of cellulose ethers, such as methylcellulose and carboxymethylcellulose suggests that these agents are effective as bulk laxatives. Their mechanism of action involves increasing both the water content of, and the bulk content of the stool, as well as lubricating the stool; thereby relieving constipation.
Cellulose ethers have been administered as bulk laxatives in dosage forms comprising of tablets, suspensions, and bulk powders; the latter as sugar-free or in compositions containing high amounts of sugar.
Cellulose ethers administered as suspensions in water may contain high concentrations of sucrose or other sugars and flavors. In such formulations, the sugar competes with the cellulose ether for available water, thereby preventing the cellulose ether from hydrating sufficiently to form a gel. The advantages of using a suspension formulation is that the cellulose ether is dispersed sufficiently to avoid any significant lumping in the digestive tract. However, these suspensions are viscous, semi-gelatinous, and visually unappealing to the consumer. Another disadvantage is the unpalatability of the suspensions due to the slimy mouth feel and extreme sweetness of such suspensions. Hence, these dosage forms have not gained significant consumer acceptance.
Bulk powders of cellulose ethers often exhibit lumping of individual particles and gelation and thus, remain undissolved as they pass through the digestive tract. Additionally, administration of bulk powders has caused cramping, nausea, and vomiting in some patients. Therefore, bulk powders are not the preferred dosage form for cellulose ethers.
Palatable and visually appealing bulk powders have, however, been accomplished by addition of water or another aqueous liquid to a dry powder mix of a water-soluble cellulose ether and a dispersing agent/sweetening component, typically sugar. This technology is disclosed in South African patent No. 84,1044, published Sep. 26, 1984. The pitfall with these compositions is that they contain about 400 calories of nutritive value per dose, primarily due to the high sugar content. This high caloric value is not acceptable to the average consumers or to users suffering from blood sugar disorders, including diabetics. Elderly people are normally, the common strata of the population that suffers from constipation and the more frequent users of laxatives, and are also commonly suffering with blood sugar disorders. The consumption of large quantities of sugar could aggravate blood sugar disorders.
Sugar encrusted cellulose ethers have been proposed as alternatives to the bulk powders containing high amounts of sugar. Such formulations have 1) less sugar such as natural sugar or combination of sugars such as sucrose, glucose, fructose or corn syrup solids; 2) lower caloric value; and 3) are readily dispersed in cold aqueous liquids.
Citrucel® Orange Flavor, a bulk forming laxative containing methylcellulose as its active ingredient, was first introduced into the market in 1986. This product contains 15 g of sucrose in a 19 g adult dose, which corresponds to a 2 g dose of methylcellulose. To decrease the sugar content of this product, a natural flavored formula lower in caloric value, and containing only 1 g sucrose, was developed and introduced in 1988. Additional patent protection for this product has focused on producing a sugar-free and virtually calorie-free powder. The product has a sugar-free sweetener, a dispersing agent, other excipients, and flavoring and was marketed in 1991 as Sugar Free Citrucel® Orange Flavor.
There still remains a need in the art to develop a rapidly disintegrating solid dosage form of a bulk agent, preferably methylcellulose, which is convenient to take and transport, sugar free, and easily administered to the consumer having blood sugar disorders or diabetics, for instance.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for preparing methylcellulose tablets which are readily dispersible and meet United States Pharmacopoeia standards for disintegration. The methylcellulose is compressed into tablets which contain an edible calcium salt, in preferred w/w ratios. Preferably the tablets rapidly disintegrate, in-vitro in 0.1N hydrochloric acid and water at 37±0.5° C.
DETAILED DESCRIPTION OF THE INVENTION
There is a common belief that tabletted cellulose ethers do not readily dissolve in the digestive tract because these cellulose ethers are highly hygroscopic. The outer portion of the tablet is said to form a gel-like hydrate that prevents the tablet from breaking up and greatly retards the hydration of the inner portion of the tablet. The present invention overcomes this art recognized problem and involves preparation of a novel composition, and process of making, by which a rapidly disintegrating tablet of methylcellulose is prepared.
The tablets are prepared by a novel process involving a high-shear wet granulation method, followed by fluidized bed drying, milling, mixing with the other ingredients, and compression.
The present invention is to a methylcellulose tablet which comprises methylcellulose having a viscosity of >1000 centipoise, and at least one excipient selected from an edible calcium salt. It is recognized that the formulation will also include diluents and fillers well known to the skilled artisan.
The tablet formulations of the present invention are advantageous over other dosage forms of methylcellulose because of their convenience of administration and rapid disintegration. This is in contrast to tablets of methylcellulose, formulated as 100% w/w methylcellulose in a 0.5 gm caplet which have been found not to disintegrate in 0.1N HCl solution, using a conventional dissolutiogn apparatus even after two hours. The present tablets should disintegrate in 0.1N HCl from about 20 to about 30 minutes, preferably from about 10 to about 19 minutes, and more preferably less than 10 minutes; and in water, the tablets should disintegrate from about 25 to about 30 minutes, preferably from about 15 to about 24 minutes, and more preferably less than 15 minutes.
It has been found that low molecular weight (mw) methylcellulose is less effective for use as a laxative, and therefore is less desirable for use in a rapidly disintegrating tablet formulation. Higher molecular weight methylcellulose is therefore both desirable and necessary in the present invention. The fibers must have a sufficient viscosity to gel and retain water in the gut to provide the stool bulking and softening for laxation use.
By using the testing methods for methylcellulose under standard conditions, such as those found in the USP XXII, p. 894, Apparent Viscosity method for Methylcellulose, or as discussed in Handbook of Pharmaceutical Excipients, APhA, a preferred methylcellulose for use herein should have a viscosity of >1000 centipoises (cps), preferably >2000 centipoises, more preferably >3000 centipoises, and most preferably >4000 centipoise. Higher molecular weight methylcellulose than those described is also desirable, however, the commercially availability of this grade of methylcellulose being the limiting feature. At present the upper limit commercially available is about 6000 cps, which is encompassed within the scope of this invention. One presently available methylcellulose product for use herein is Methocel A4M, made by Dow Chemical Company, Midland Mich. as Dow Methocel A4M, having a viscosity of about 3000 to about 5,600 cps, which is within 75 to 140% of the desired target viscosity herein.
Some of the additional diluents or fillers for use in this formulation are preferably swellable agents, and may include, but are not limited to, various grades of microcrystalline cellulose, such as Avicel PH101, Avicel PH102, & Avicel PH200; Corn starch; or Starch 1500.
The edible calcium salts suitable for use herein include but are not limited to, dibasic calcium phosphate dihydrate, calcium phosphate anhydrous, and tribasic calcium phosphate; or mixtures thereof. A preferred edible calcium salt is the dibasic calcium phosphate dihydrate salt, which salt also provides good compressibility.
If microcrystalline cellulose is added, it is preferably from about 50 to 180 microns in size, more preferably about 50. Avicel PH 101 has a mean particle size of about 50; Avicel PH 102 has a mean particle size of about 100; and Avicel PH 200 has a mean particle size of about 190 microns. Preferably the preferred microcrystalline cellulose is Avicel PH 101.
It is noted that the ratio of methylcellulose to edible calcium salt, and additional diluents will depend upon the diluent chosen, and is within the skill of the art to determine with preciseness the necessary ratios.
Suitable ratios for particular diluents however, are described below:
For Methylcellulose:Dibasic calcium phosphate, dihydrate, from about 2 to about 4:1, preferably from about 2.6-3.1:1;
For Methylcellulose:Calcium phosphate, anhydrous from about 2 to about 4:1, preferably from about 3.1:1
Methylcellulose:Tribasic calcium phosphate, WG® from about 2 to about 4:1, preferably from about 3.1:1
For Methylcellulose:microcrystalline cellulose, from about 2:1 to about 14:1. Preferably for Avicel PH 101 from about 2.2-13.5:1; for Avicel PH 102 from about 2.4-8.3:1; and for Avicel PH 200 from about 2.44:1.
For Methylcellulose:Corn starch from about 7.5 to about 15, preferably from about 13.5:1;
For Methylcellulose:Starch 1500 , from about 2.0 to about 5.0:1, preferably from about 2.4:1;
For Methylcellulose:Explotab, from about 5 to about 25:1, preferably from about 8.1 to about 21.3:1.
It is recognized that with the edible calcium salt, the formulation must also have an ingredient which keeps the granules together, i.e. a binding agent. A preferred binding agent is PVP, or the alternative agents noted below.
In addition to the above noted edible calcium salt(s), optional diluents or fillers, and binding agent(s), the formulation may also include additional components such as, but are not limited to, a wetting agent, (super)disintegrant(s), a second binding agent(s), dye(s) or colouring agents, and lubricants, which are preferably used to prepare a tablet that is wetted readily, and is rapidly disintegrated in 0.1N hydrochloric acid and water, the USP test standard test for methylcellulose.
A preferred wetting agent is sodium lauryl sulfate.
A preferred lubricant is magnesium stearate.
A preferred binding agent is polyvinylpyrrolidone, or PVP, such as Povidone 29K/32. Preferably, the PVP is present in an amount of about 4 to about 6.5% w/w.
A preferred disintegrating agent is sodium starch glycolate, such as Explotab®. Preferably, the sodium starch glycolate is present in an amount of about 3 to about 8% w/w.
As various excipents and diluents will be formulated together, and used in combination herein, suggested % w/w ratios for various formulations are presented below. While not all of these ratios include the edible calcium salts, these are merely illustrative of the invention and the skilled artisan will readily recognize how to formulate the product of this invention with the addition of the edible calcium salts.
Sodium lauryl sulfate:Explotab:Dibasic calcium phosphate, dihydrate:Povidone 29K/32:Magnesium stearate include: 0.38-0.40:3.5-7.9:20.6-24.8:4.0-6.5:0.5-1.0
Sodium lauryl sulfate:Explotab:Tribasic calcium phosphate WG®:Povidone 29K/32:Magnesium stearate include: 0.40:3.5:21.6:6.4:1.0
Sodium lauryl sulfate:Explotab:Calcium phosphate, anhydrous:Povidone 29K/32:Magnesium stearate include: 0.40:3.5:21.6:6.4:1.0
Methylcellulose:sodium lauryl sulfate (SLS), from about 60 to about 170:1, preferably from about 155:1-170:1;
Methylcellulose:Povidone, preferably PVP 29K/32, from about 8 to about 22:1, preferably from about 10.4:1-16.7:1;
Methylcellulose:Magnesium stearate from about 50 to about 150;1, preferably from about 58-132:1;
Sodium lauryl sulfate:Explotab:Avicel PH 101®:Povidone 29K/32:Magnesium stearate include: 0.35-0.46:3.05-6.17:4.38-27.13:4.38-6.66:0.76-1.14
Sodium lauryl sulfate:Explotab:Avicel PH 102®:Povidone 29K/32:Magnesium stearate include: 0.35-0.46:4.9-6.17:9.21-25.53:4.38-6.66:0.76-1.14
Sodium lauryl sulfate:Avicel PH 200(:Povidone 29K/32:Magnesium stearate include: 0.38-0.42:19.27-25.53:5.99-6.66:0.94-1.04
Sodium lauryl sulfate:Explotab:Corn starch:Povidone 29K/32:Magnesium stearate include: 0.36-0.38:3.66-7.07:4.35-4.68:4.35-4.68:0.88-0.95
Sodium lauryl sulfate:Explotab:Starch 1500®:Povidone 29K/32:Magnesium stearate include: 0.36-0.38:3.66-7.07:24.05-25.89:4.35-4.68:0.88-0.95
Not wishing to be limited to the explicit excipients noted above, the following alternative agents may also be used herein.
Alternatives lubricants to magnesium stearate include, but are not limited to, calcium stearate, sodium stearate, Cab-O-Sil, Syloid, stearic acid and talc.
Alternatives binding agents to PVP include but are not limited to, hydroxypropylcellulose, hydroxypropyl methylcellulose, acacia, gelatin, tragacanth, pregelatinized starch and starch.
Alternatives disintegrants to Explotab® include but are not limited to, sodium carboxymethylcellulose, Ac-di-sol®, carboxymethylcellulose, veegum, alginates, agar, guar, tragacanth, locust bean, karaya, pectin, and crospovidone.
Alternative wetting agents to sodium lauryl sulfate, include but are not limited to, magnesium lauryl sulfate.
All of these formulations can be prepared with and without sugar. A sugar-free formulation has the advantage that it can be administered easily to consumers with blood sugar disorders or to diabetics in need of such preparations.
Another advantageous property of the present invention is that the formulations contain calcium, such as dibasic calcium phosphate dihydrate. These formulations, for instance, will contain approximately an 80 mg/dose, anticipating formulating a 0.5 gm/tablet×2 tablets/dose of methylcellulose. If desired the amount of calcium can be increased in these tablets to provide increased therapeutic value to the consumer.
The amount of methylcellulose present in each dose, as well as the number of doses of laxative taken per day, will depend somewhat on the age, sex, size of the patient, severity of the patient's particular problem, the advice of the treating physician, if any, and the particular taste and habits of the patient. Accordingly, the tablets of this invention are advantageously administered in a single dose which may contain as much as 500 to 1000 mg of methyl cellulose tablet, or in a plurality of smaller doses containing as little as 250 mg per tablet. Most preferably, for laxative effect, each tablet will contain about 500 mg methylcellulose and the patient may take 1 to 2 tablets per dose. This dosage, of 1000 mg should adequately provide optimal laxative efficacy. Therefore, a preferred range of methylcellulose per tablet is optimally from about 450 to 550 mg, preferably about 500 mg; or alternatively from about 200 to about 300 mg for a smaller tablet, preferably about 250 mg; or even in increments of about 125 mg tablet, i.e. 75 to 175 mg per tablet.
While preferably the compressed tablets are uncoated, they may, if desired, be coated with any suitable coating agent well known in the art. Suitably the coating agents are those used for immediate release purposes and will dissolve in the gastric juices. Such coating agents are well known to those skilled in the art and include, but are not limited to hydroxypropyl methylcellulose, or methyl cellulose, or 20% w/w Opadry II, orange in water.
As will readily be seen by the working examples, there are various combinations of intra and extragranular mixing which are possible using the ingredients herein. All are encompassed within the scope of this invention. Generally, the high viscosity methylcellulose, such as Methocel A4M, will first be granulated with a binder, such as povidone, a wetting agent, such as sodium lauryl sulfate, and a suitable colouring agent to form the intragranular mixture which is then granulated. These granular components are then admixed with additional wetting agents, and disintegrating agents and finally blended with lubricant. This final granular mixture is then blended and compressed into the tablets of the present invention.
Therefore, an aspect of the present invention is a process for preparing a tablet formulation which comprises
a) blending together to form an intragranular mixture high viscosity methylcellulose of >3000 cps, a wetting agent, povidone or sodium starch glycolate, and an edible calcium salt; and
b) adding to the mixture of step (a) a PVP aqueous solution, or alternatively spraying the mixture of step (a) with a PVP aqueous solution; and preparing granulates; and
c) blending together an extragranular mixture of an edible calcium salt, a wetting agent; a lubricating agent; povidone or sodium starch glycolate or a mixture thereof; and
d) compacting the granulates of step (b) with the extragranular mixture of step (c).
Another aspect of the present invention is a process for the manufacture of a pharmaceutical tablet, which process comprises mixing
a) granulates comprising high viscosity methylcellulose of >3000 cps, a wetting agent, povidone or sodium starch glycolate, an edible calcium salt; and
b) blending together an extragranular mixture of an edible calcium salt, a wetting agent; a lubricating agent; povidone or sodium starch glycolate or a mixture thereof; and
c) compacting the granulates of step (b) with the granular mixture of step (a); and
d) compressing into a tablet.
Another aspect of the present invention is the method of relieving constipation by increasing the water content of the stool, or by providing a lubricating effect on the stool in a mammal in need thereof, which method comprises administering to said mammal, an effective amount of a high viscosity methylcellulose compressed into a tablet with a suitable diluent.
METHODS OF PREPARATION
The following examples illustrates the invention but is not intended to limit the scope thereof. All parts and percentages are by weight unless otherwise indicated. The disintegration time of the formulations described in the Tables below were obtained by using a conventional disintegration apparatus.